Endocannabinoids in neurodegenerative diseases

摘要 痴呆症在美国影响着数百万人。阿尔茨海默病(AD)是最常见的 老年人痴呆症的病因。然而，目前还没有有效的治疗方法来预防和 治疗阿尔茨海默病或阻止疾病的进展。因此，开发有效的治疗方法势在必行。 广告。尽管阿尔茨海默病的病因是多因素和复杂的，但积累的证据表明 神经炎症是包括阿尔茨海默病在内的神经退行性疾病的根本原因。因此，解决 神经炎症对于预防AD的发展或改变疾病的进展至关重要。 内源性大麻素是一种天然存在的生物活性脂质介质，参与多种生理和 病理过程。2-花生四烯基甘油(2-AG)是一种含量最丰富的内源性大麻素，具有丰富的生物活性。 具有抗炎和神经保护作用。药物失活对2-氨基酚降解的抑制作用 单甘油脂肪酶(MAGL)是大脑中降解2-AG的关键酶，已被证明能产生 在AD中具有神经保护作用，因此MAGL已被认为是AD的治疗靶点。在.期间 目前的资助期，我们发现MAGL的遗传失活减少了神经病理并避免了 在创伤性脑损伤的动物模型中，突触和认知能力下降。令人惊讶的是，这些 神经保护作用主要是由于星形胶质细胞中2-AG信号的增强，而不是神经元。 提示MAGL失活对脑损伤的神经保护作用是通过2-AG介导的。 神经炎的特定细胞类型的消解。在这项相互竞争的续期申请中，我们建议 确定MAGL基因失活是否具有抗炎和神经保护作用 阿尔茨海默病的动物模型以及保护作用是否也是细胞类型特异性的。为了实现这一目标，我们将 评估β-淀粉样蛋白(Aβ)和tau蛋白的神经病理，突触的结构和功能可塑性，以及认知 细胞类型特异性失活MAGL在AD动物模型中的作用及分子描述 MAGL失活的机制--在AD中产生神经保护作用。其结果是 拟议的研究将使我们能够更好地开发有效的治疗方法或改进治疗方法 广告。

Summary Dementia affects millions of people in the United States. Alzheimer’s disease (AD) is one of the most common causes of dementia in elderly. However, there are no effective therapies currently available for preventing and treating AD or halting progression of the disease. Therefore, it is imperative to develop efficacious therapies for AD. Although the etiology of AD is multifactorial and complex, accumulated evidence suggests that neuroinflammation is a root cause of neurodegenerative diseases, including AD. Hence, resolving neuroinflammation is crucial for preventing development of AD or for modifying disease progression. Endocannabinoids are naturally occurring bioactive lipid mediators involved in a variety of physiological and pathological processes. 2-Arachidonoylglycerol (2-AG), the most abundant endocannabinoid, displays profound anti-inflammatory and neuroprotective properties. Inhibition of 2-AG degradation by pharmacological inactivation of monoacylglycerol lipase (MAGL), the key enzyme that degrades 2-AG in the brain, has been shown to produce neuroprotective effects in AD, and thus MAGL has been proposed as a therapeutic target for AD. During the current funding period, we discovered that genetic inactivation of MAGL reduces neuropathology and averts synaptic and cognitive declines in an animal model of traumatic brain injury (TBI). Surprisingly, these neuroprotective effects result primarily from augmentation of 2-AG signaling in astrocytes, rather than in neurons, suggesting that the neuroprotective effects induced by inactivation of MAGL in TBI are through 2-AG-mediated cell type-specific resolution of neuroinflammation. In this competing renewal application, we propose to determine whether genetic inactivation of MAGL produces anti-inflammatory and neuroprotective effects in animal models of AD and whether the protective effects are also cell type-specific. To reach this goal, we will assess beta-amyloid (Aβ) and tau neuropathology, structural and functional plasticity of synapses, and cognitive function by cell type-specific inactivation of MAGL in animal models of AD and delineate the molecular mechanisms that contribute to the MAGL inactivation-produced neuroprotective effects in AD. The outcome of the proposed research will enable us to better development of efficacious therapies or to refine treatments for AD.